Michael Behe first used the term "irreducible complexity" in his 1996 book Darwin's Black Box, to refer to certain complex biochemical cellular systems. He posits that evolutionary mechanisms cannot explain the development of such "irreducibly complex" systems. [...] Intelligent design advocates argue that irreducibly complex systems must have been deliberately engineered by some form of intelligence.

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Most intelligent design advocates accept that evolution occurs through mutation and natural selection at the "micro level", such as changing the relative frequency of various beak lengths in finches, but assert that it cannot account for irreducible complexity, because none of the parts of an irreducible system would be functional or advantageous until the entire system is in place.

Behe uses the mousetrap as an illustrative example of this concept. A mousetrap consists of several interacting pieces—the base, the catch, the spring, the hammer. Behe contends that all of these must be in place for the mousetrap to work, and that the removal of any one piece destroys the function of the mousetrap. Likewise, biological systems require multiple parts working together in order to function. Intelligent design advocates claim that natural selection could not create from scratch those systems for which science is currently not able to find a viable evolutionary pathway of successive, slight modifications, because the selectable function is only present when all parts are assembled. Behe's original examples of irreducibly complex mechanisms included the bacterial flagellum of E. coli, the blood clotting cascade, cilia, and the adaptive immune system.

Behe argues that organs and biological features which are irreducibly complex cannot be wholly explained by current models of evolution. He argues that:

An irreducibly complex system cannot be produced directly (that is, by continuously improving the initial function, which continues to work by the same mechanism) by slight, successive modifications of a precursor system, because any precursor to an irreducibly complex system that is missing a part is by definition nonfunctional.

In a magnificent paper, Bridgham, Carroll and Thornton (BCT, 4) have tackled the daunting task of reconstructing evolutionary pathways head on, reconstructing ancient proteins in the process. The article looks at one of Behes key examples, protein-binding sites for small molecules. The ability of proteins to bind small molecules is critical for organisms to function, because enzymes bind small molecules as part of metabolism, receptors proteins bind small hormone molecules to initiate cell signaling and many small molecules bind to a variety of proteins to modify their functions.

For example, in the Behe and Snoke paper (3), they examine the ability of the oxygen carrying protein haemoglobin to bind the organic phosphate molecule 2,3-diphosphoglycerate (DPG, which modifies the oxygen binding capacity of haemoglobin). The BCT paper looks at the binding site of the receptors for some steroid hormone receptors, those for mineralocorticoids (MR) and those for glucacorticoids (GR). Receptors are proteins whose amino acid chains fold in such a way as to produce a pocket where particular small molecules (hereafter called ligands) bind. These pockets can be incredibly selective, and the term "lock and key" is often used. The small molecule fits into the protein receptor like a key into a lock (this is an oversimplification, as the molecules are flexible, and are "floppy" keys and locks, and the electrostatic charge and lipid solubility of the molecule comes into play, but it helps visualization).

Now, modern tetrapods (amphibians, reptiles, birds and mammals) have separate receptors for the steroid hormones cortisol (GR, which modulates metabolism, inflammation and immunity) and aldosterone (MR, modulates salt balance amongst other things). Hagfish and Lampreys ("primitive" jawless fish with cartilaginous skeletons) have only one receptor, which is activated by both aldosterone and cortisol. Sharks and such have two receptors, both of which are activated by both aldosterone and cortisol. Finally, bony fish and tetrapods have two receptors, one which is activated by aldosterone, and one which is activated by cortisol. What were the molecular steps which brought this about?

BCT approach this in a very elegant way. Using phylogenetic analysis of the existing sequences of GR and MR receptors they were able to reconstruct the sequence of the receptor ancestral to the GR and MR. They expressed this reconstructed gene in cells, and tested the sensitivity to aldosterone and cortisol. The ancestral receptor responded to both aldosterone and cortisol. By a combination of phylogenetic analysis and mutagenesis they isolated two mutations that converted the ancestral receptor into a GR (serine to proline at position 106 in the chain, and lysine to glutamine at position 111). By studying their properties, and comparing them to MR and GR receptors from hagfish, sharks, bony fish and tetrapods, they determined that the seriene to proline mutation came first, followed by the lysine to glutamate.

"So the point is that those little colored squares [amino acids] are enormously complex in themselves, and further the ability to get them to bind specifically to their correct partners also requires much more additional information. It is not a single step phenomenon. You have to have the surfaces of two proteins to match."

What is the irreducibly complex system that Bridgham et al. wish to explain? In particular,

(a) What is the system's function?(b) What are the system's "several well-matched, interacting parts?"(c) What happens when one of those parts is removed?A logical point: since irreducible complexity [IC] as a biological phenomenon is defined by criteria a, b, and c, any claim to have demonstrated the stepwise (Darwinian) pathway to an IC system must begin by describing that system in terms of (a) its function, (b) its parts list, and (c) the consequences when one of the parts is removed. [Hervorhebung aus dem Original]

Indeed, given that natural selection favors only functionally advantageous variations, Behe has made clear that “function” in a biological context necessarily means a selectable functional advantage, for an obvious reason: a system of well-matched parts that performs a function can’t lose that function unless it possesses one to begin with. Unfortunately, these receptor-ligand pairs do not meet Behe’s definition of irreducible complexity for an equally obvious reason: receptor-ligand pairs do not by themselves confer any selective functional advantage.[Hervorhebung in grau aus dem Original]

Indeed, in Bridgham et al.’s scenario, the function undergoing natural selection is not simply MR-aldosterone binding, but electrolyte homeostasis, the complex physiological regulation of essential cellular ions such as potassium or calcium. The novel receptor MR evolved, they write, “because it allowed electrolyte homeostasisto be controlled” (p. 100). Natural selection is acting, therefore, not on MR-aldosterone binding alone. Indeed, it cannot, because unspecified binding confers no functional advantage. But that is what Bridgham et al. do not seem to understand. They think they are explaining the origin of a single receptor-ligand pair, the mineralocorticoid receptor (MR) protein and the steroid hormone aldosterone. But that is biological nonsense. It is nonsense, moreover, strictly on the grounds of evolutionary theory itself.

Who knows? Without more information -- that is, without more details about the cellular or organismal effect of that novel binding -- the bare function “aldosterone binds to MR” is biologically vacuous.[Hervorhebungen in grau aus dem Original]

Here, we formulate a similar hypothesis to explain the emergence of complexity in biological pathways: Pathways have an intrinsic tendency to become more complex that results from imbalanced effects of mutational events on pathway response. In other words,mutations resulting in the addition of new interactions or proteins to a given pathway have less deleterious effects on its response than mutations that result in loss of interactions or proteins.If such an imbalance exists, it would drive pathways to become larger and more complex in time. To test this hypothesis, we analyze evolution of pathways by using mathematical models and computer simulations. Starting with a population of small pathways, we let pathways replicate with various mutations affecting their structure.

Und sie kommen zu dem Schluss:

To summarize, the key finding of the presented study is that there is an imbalance between the effects of size-decreasing and -increasing mutations on pathway response, the amount of which is related to pathway size and the selection criterion. It is important to note that the ability of such imbalance to produce complexity will depend on the cost of maintaining additional proteins in the pathway and the assumptions regarding the frequency of size-increasing and -decreasing mutations.

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These findings have implications for our understanding of the evolution of new features. For example, in simulating the evolution of a random population of three-protein pathways under selection for responding to a given signal, we reach a structurally diverse population with an average pathway size of ~14 proteins [ausgehend von drei Proteinen]. Given the exponential relation between pathway size and available pathway topologies,it is plausible to assume that such growth would facilitate the emergence of pathways with various response dynamics that would not have been possible with three proteins only. If such pathways achieve new functions or high-fitness solutions under the current selection criterion, they would be strongly selected. Hence, even though complexity can emerge neutrally, once it results in evolutionary favorable pathways, it may be maintained subsequently by selection.